1. Field of the Invention
The present invention relates to estra-1,3,5(10),16-tetraene derivatives or pharmaceutically acceptable salts thereof, which show inhibitory activity against steroid sulfatase and are useful in treating or preventing hormone dependent diseases.
2. Brief Description of the Background Art
In post-menopausal women, estrogen levels in breast tumors are is at least ten times higher than those in plasma, and such high estrogen levels in breast tumors are caused by the function of steroid sulfatase (estrone sulfatase) which hydrolyzes estrone sulfate into estrone. Consequently, steroid sulfatase inhibitors are effective therapeutic agents in treating estrone dependent breast cancers and are also considered to be effective in preventing or treating other diseases concerned by estrones, such as endometrial cancers, ovarian cancers, prostate cancers, and adenomyosis of uterus.
Estrone-3-sulfamate (EMATE) has been reported as a typical inhibitor of steroid sulfatase (International Journal of Cancer, 63: 106 (1995); U.S. Pat. No. 5,616,574). However, it has been revealed recently that EMATE shows an estrogenic activity, and it is shown that EMATE is not useful for the treatment of estrone dependent diseases (Cancer Research, 56: 4950 (1996)).
Examples of other known steroid type of steroid sulfatase inhibitors include estrone-3-methylthiophosphonate, estrone-3-methylphosphonate, estrone-3-phenylphosphonothioate, and estrone-3-phenylphosphonate (Cancer Research, 53: 298 (1993); Bioorganic & Medicinal Chemistry Letters, 3: 313 (1993); U.S. Pat. No. 5,604,215), estrone-3-sulfamate derivatives (Journal of Medicinal Chemistry, 37: 219 (1994)), 3-desoxyestrone-3-sulfonate derivatives (Steroids, 58: 106 (1993); The Journal of Steroid Biochemistry and Molecular Biology, 50: 261 (1994)), 3-desoxyestrone-3-methylsulfonate derivatives (Steroids, 60: 299 (1995)), estrone-3-amino derivatives (The Journal of Steroid Biochemistry and Molecular Biology, 59: 83 (1996); U.S. Pat. No. 5,571,933; U.S. Pat. No. 5,866,603), vitamin D.sub.3 derivatives (The Journal of Steroid Biochemistry and Molecular Biology, 48: 563 (1994)), dehydroepiandrosterone derivatives (The Journal of Steroid Biochemistry and Molecular Biology, 45: 383 (1993); Biochemistry, 36: 2586 (1997)), A-ring modified derivatives of estrone-3-sulfamate (The Journal of Steroid Biochemistry and Molecular Biology, 64: 269 (1998); WO 98/24802; WO 98/32763), 17-alkylestradiol derivatives (Bioorganic & Medicinal Chemistry Letters, 8: 1891 (1998)), 3-substituted-D-homo-1,3,5(10)-estratriene derivatives (WO 98/11124), D-ring modified derivatives of estrone (WO 98/42729), and B-,C- and D-ring modified derivatives of estrone (Canadian Journal of Physiology and Pharmacology, 76: 99 (1998)).
Examples of known non-steroid type of steroid sulfatase inhibitors include tetrahydronaphthol derivatives (Journal of Medicinal Chemistry, 37: 219 (1994)), 4-methylcoumarin-7-sulfamate (Cancer Research, 56: 4950 (1996); WO 97/30041), tyramine derivatives and phenol derivatives (Cancer Research, 57: 702 (1997); Biochemistry, 36: 2586 (1997); The Journal of Steroid Biochemistry and Molecular Biology, 68: 31 (1999); U.S. Pat. No. 5,567,831), flavonoids (The Journal of Steroid Biochemistry and Molecular Biology, 63: 9 (1997); WO 97/32872), and 4-hydroxytamoxifen derivatives (The Journal of Steroid Biochemistry and Molecular Biology, 45: 383 (1993); Bioorganic & Medicinal Chemistry Letters, 9: 141 (1999)).
It is also reported that steroid sulfamates and tyramine derivatives have the effect of memory enhancement (U.S. Pat. No. 5,556,847; U.S. Pat. No. 5,763,492).
Also, it has been reported recently that certain 17-amide derivatives, such as 17.beta.-(N-alkylcarbamoyl)estra-1,3,5(10)-triene-3-sulfamates and 17.beta.(N-alkanoyl)estra-1,3,5(10)-triene-3-sulfamates (Steroids, 63: 425 (1998); WO 99/03876), show inhibitory activity against steroid sulfatase.
The following 17-amide derivatives (Compound A) described in WO 99/03876 are synthetic intermediates of compounds in which the phenolic hydroxyl group at the 3-position is substituted with sulfamoyloxy, and the substituent on the amide group is limited to straight chain alkyl having 4 or more carbon atoms. It is not known that Compound A shows inhibitory activity against steroid sulfatase. ##STR2##
(In the above formula, R.sup.2p represents straight-chain alkyl having 4 to 14 carbon atoms; X.sup.P represents methine, or forms a double bond together with Y.sup.P ; and Y.sup.P represents methylene, or forms a double bond together with X.sup.p.)
Additionally, as examples of Pd-catalyzed carbonylation and as synthetic intermediates of steroid 5.alpha.-reductase, 17-amide derivatives and 17-carboxylic acid derivatives (Compound B) shown below in which a hydroxyl group at the 3-position is substituted with methoxy, trifluoromethanesulfonyloxy, acetoxy, methanesulfonyloxy, or benzoxy, have been reported (for example, Tetrahedron Letters, 26: 1109 (1985); Tetrahedron Letters, 33: 3939 (1992); Journal of Medicinal Chemistry, 33: 937 (1990); Journal of Medicinal Chemistry, 33: 943 (1990); Synthesis, 831 (1995); Helvetica Chimica Acta, 81: 2264 (1998); U.S. Pat. No. 4,946,834 and 4,910,226). Compound C in which a double bond is reduced is also known (for example, The Journal of Organic Chemistry, 59: 6683 (1994); WO 93/14107; WO 95/21185; WO 97/40062). However, it has not been reported that any of these compounds shows inhibitory activity against steroid sulfatase. ##STR3##
(In the above formulae, when X.sup.q and Y.sup.q are combined to represent a double bond, R.sup.1P represents hydroxy, isopropoxy, methoxy, 2-iodo-4-methylphenoxy, or NR.sup.2q R.sup.3q (wherein R.sup.2q and R.sup.3q are the same or different, and each represents hydrogen, ethyl, isopropyl, or tert-butyl, or R.sup.2q and R.sup.3q are combined together with the adjacent nitrogen atom to represent pyrrolidinyl, morpholino, or piperidino), and R.sup.4q represents methyl, trifluoromethanesulfonyl, acetyl, methanesulfonyl, or benzoyl. When X.sup.q is methine and Y.sup.q is methylene, R.sup.1P represents methoxy or NR.sup.2R R.sup.3r (wherein R.sup.2r and R.sup.3r are the same or different, and each represents hydrogen, isopropyl, or substituted alkyl), and R.sup.4p represents methyl, trifluoromethanesulfonyl, or methanesulfonyl. R.sup.1q represents hydroxy or NR.sup.2s R.sup.3s (wherein R.sup.2s and R.sup.3s are the same or different, and each represents hydrogen, isopropyl, tert-butyl, or substituted alkyl).)
Steroid sulfatase inhibitors, which do not show estrogenic activity, and are more metabolically stable and more selective for the enzyme, are desired.